The goal of this research is to understand the role of serotonin in female sexual behavior. The PI's previous work has focussed on identification of neural sites for the action of specific 5HT receptor subtypes involved in the mediation of the lordosis response. She has identified the VMN as a site for 5HT action and has shown that 5HT1A and 5HT2A/2C receptor subtypes respectively inhibit and facilitate lordosis. The current proposal will continue this line of inquiry, focussing on the idea that 5HT has dual effects on lordosis, and that these two receptor subtypes, 5HT1A and 5HT2A/2C, act in concert to modulate receptivity. The PI has hypothesized that it is the activation of 5HT1A sites in the VMN that are attenuated on proestrus, and the 5HT2A/2C receptor activation attenuates the lordosis-inhibiting effects of 5HT1A receptors. She has developed several testable predictions from this hypothesis. Some of these have already been tested and are reported in the preliminary data section. The others make up the body of this proposal. The revised application has seven aims. The first three aims involve testing the effects of various 5HT1A and 5HT2A/2C agonists and antagonists in the suboptimally hormone-primed ovariectomized rat to get at the generality of these dual serotonergic effects. The last four aims are designed to investigate the mechanism by which 5HT1A receptor agonists inhibit lordosis and 5HT2A/2C agonists facilitate lordosis. The two mechanisms to be tested are G-protein coupling to adenylyl cyclase and G-protein coupling to K+ channels. These choices are based on reports that agents which inhibit adenylyl cyclase inhibit lordosis while agents which facilitate the phosphoinositide system facilitate lordosis.
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